title: γ-Tocotrienol induced cell cycle arrest and apoptosis via activating the Bax-mediated mitochondrial and AMPK signaling pathways in 3T3-L1 adipocytes.
abstract: This study aimed to examine the anti-proliferative effects of α-, γ- and δ-tocotrienols (αT3, γT3 and δT3), and α-tocopherol on 3T3-L1 adipocytes. Results showed that compared with other vitamin E analogues, γT3 demonstrated the most potent anti-proliferative effect on 3T3-L1 cells. It significantly caused a reduction in mitochondrial membrane potential (Δψm) and an increase in ROS formation, as well as inducing cell apoptosis and cell cycle arrest at S phase. Further studies showed that it down-regulated Bcl-2 and PPAR-γ expression, suppressed Akt and ERK activation and phosphorylation, and caused cytochrome c release from mitochondria to cytosol, whereas it up-regulated CD95 (APO-1/CD95) and Bax expression, and caused caspase-3 and JNK activation, PARP cleavage and AMPK phosphorylation. Pretreatments with caspase-3 (z-DEVD-fmk) and AMPK (CC) inhibitors significantly suppressed the γT3-induced ROS production and cell death. Caspase-3 inhibitor also efficiently blocked CD95 (APO-1/CD95) and Bax expression, caspase-3 activation and PARP cleavage, whereas antioxidant N-acetyl-l-cysteine, AMPK inhibitor and AMPK siRNA effectively blocked the AMPK phosphorylation. Taken together, these results conclude that the potent anti-proliferative and anti-adipogenic effects of γT3 on 3T3-L1 adipocytes could be through the Bax-mediated mitochondrial and AMPK signaling pathways.
authors.affiliation: Department of Nutritional Health, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Shu-Jing
authors.initials: SJ
authors.lastname: Wu
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Huang
authors.forename: Lean-Teik
authors.initials: LT
authors.lastname: Ng
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D052438:Adipocytes, White / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D019440:Anti-Obesity Agents / Q000378:metabolism; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D002839:Chromans / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019587:Dietary Supplements; D015536:Down-Regulation; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000819:agonists / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; C494827:Bax protein, mouse; D002839:Chromans; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D014810:Vitamin E; C013649:plastochromanol 8; D055372:AMP-Activated Protein Kinases
keywords: 3T3-L1 adipocytes; AMPK; Adipogenesis; Apoptosis; Tocotrienols